The overall goal of this work is to expand our understanding of the basic pathophysiology of neurological morbidity in anemia using novel MRI-derived measures of oxygen extraction fraction (OEF). Sickle cell anemia (SCA) is a well-characterized monogenetic disorder with an abnormal form of hemoglobin (Hb) S that leads to many complications including a high prevalence of cerebral vasculopathy, silent cerebral infarcts, and overt strokes, 100-fold greater than other children. Secondary prevention of recurrent cerebral infarcts in children with SCA includes monthly blood transfusion therapy indefinitely. This strategy significantly reduces the risk of recurrent overt and silent strokes bu with substantial transfusion-related morbidity. Many children must be transfused to prevent one recurrent infarct. Improved abilities are required to identify and stratify children at the highest risk of stroke. The critical barrier rests with a general inability to identify underlying brain tisue-level impairment that may provide evidence-based biomarkers for stroke risk. Hemodynamic failure, measured by increased OEF (the ratio of oxygen consumed to oxygen delivered) in the brain, is associated with increased stroke risk. Limited widespread availability of methodologies for measuring OEF has prevented evaluation of OEF rigorous clinical studies in children with SCA at risk of infarct recurrence. Our team has recently demonstrated an ability to utilize MRI to measure OEF noninvasively. We propose to apply this method in children with SCA to test fundamental hypotheses about the relationships between OEF, other hemodynamic factors such as cerebral blood flow, and cerebral infarcts. in the following specific aims: 1) We will develop more accurate calibration procedures by refining our hemodynamic models to include the presence and range of hemoglobin S (20-90%), so that OEF measurements are more accurate and account for HbS variation. 2) We will apply novel OEF MRI methods, already tested in our laboratory in healthy adults and adults with SCA, to healthy children and to children with SCA to assess the relationship between OEF and CBF. We hypothesize that OEF and CBF are correlated at low OEF levels and less correlated at high OEF levels due to exhaustion of cerebral autoregulatory capacity. 3) We will apply novel OEF MRI methods to children with SCA to assess whether elevated OEF correlates more strongly than cerebral blood flow with the presence of cerebral infarct(s). Impact: Results will refine the MRI technique, report normative cerebral physiology information in children with and without SCA, and assess OEF and cerebral hemodynamics in children with SCA at high risk of recurrent cerebral infarct. The immediate goal of this work is to demonstrate the utility of OEF as an indicator of elevated hemodynamic impairment. The longer-term goal is to utilize fast, noninvasive measures of OEF to risk-stratify children with SCA who are most likely to progress and have recurrent infarcts despite receiving optimal medical management.